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author:("Das, abik")
1.  Advantages of Bayesian monitoring methods in deciding whether and when to stop a clinical trial: an example of a neonatal cooling trial 
Trials  2016;17:335.
Decisions to stop randomized trials are often based on traditional P value thresholds and are often unconvincing to clinicians. To familiarize clinical investigators with the application and advantages of Bayesian monitoring methods, we illustrate the steps of Bayesian interim analysis using a recent major trial that was stopped based on frequentist analysis of safety and futility.
We conducted Bayesian reanalysis of a factorial trial in newborn infants with hypoxic-ischemic encephalopathy that was designed to investigate whether outcomes would be improved by deeper (32 °C) or longer cooling (120 h), as compared with those achieved by standard whole body cooling (33.5 °C for 72 h). Using prior trial data, we developed neutral and enthusiastic prior probabilities for the effect on predischarge mortality, defined stopping guidelines for a clinically meaningful effect, and derived posterior probabilities for predischarge mortality.
Bayesian relative risk estimates for predischarge mortality were closer to 1.0 than were frequentist estimates. Posterior probabilities suggested increased predischarge mortality (relative risk > 1.0) for the three intervention groups; two crossed the Bayesian futility threshold.
Bayesian analysis incorporating previous trial results and different pre-existing opinions can help interpret accruing data and facilitate informed stopping decisions that are likely to be meaningful and convincing to clinicians, meta-analysts, and guideline developers.
Trial registration NCT01192776. Registered on 31 August 2010.
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-016-1480-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4957277  PMID: 27450203
Bayesian methods; Factorial trial; Hypothermia; Phase III trial; Stopping rules; Trial monitoring
2.  Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993–2012 
JAMA  2015;314(10):1039-1051.
Extremely preterm infants contribute disproportionately to neonatal morbidity and mortality.
To review 20-year trends in maternal/neonatal care, complications, and mortality among extremely preterm infants born at Neonatal Research Network centers.
Design, Setting, Participants
Prospective registry of 34,636 infants 22–28 weeks’ gestational age (GA) and 401–1500 gram birthweight born at 26 Network centers, 1993–2012.
Extremely preterm birth.
Main Outcomes
Maternal/neonatal care, morbidities, and survival. Major morbidities, reported for infants who survived more than 12 hours, were: severe necrotizing enterocolitis, infection, bronchopulmonary dysplasia, severe intracranial hemorrhage, cystic periventricular leukomalacia, and/or severe retinopathy of prematurity. Regression models assessed yearly changes, adjusting for study center, race/ethnicity, GA, birthweight for GA, and sex.
Use of antenatal corticosteroids increased from 1993 to 2012 (348/1431 [24%] to 1674/1919 [87%], p<0.001), as did cesarean delivery (625/1431 [44%] to 1227/1921 [64%], p<0.001). Delivery room intubation decreased from 1144/1433 (80%) in 1993 to 1253/1922 (65%) in 2012 (p<0.001). After increasing in the 1990s, postnatal steroid use declined to 141/1757 (8%) in 2004 (p<0.001), with no significant change thereafter. Although most infants were ventilated, continuous positive airway pressure without ventilation increased from 120/1666 (7%) in 2002 to 190/1756 (11%) in 2012 (p<0.001). Despite no improvement from 1993 to 2004, rates of late-onset sepsis declined between 2005 and 2012 for infants of each GA (median GA 26 weeks, 109/296 [37%] to 85/320 [27%], adjusted relative risk [aRR]: 0.93 [95% CI, 0.92–0.94]). Rates of other morbidities declined, but bronchopulmonary dysplasia increased between 2009 and 2012 for infants 26–27 weeks (26 weeks, 130/258 [50%] to 164/297 [55%], p<0.001). Survival increased between 2009 and 2012 for infants 23 weeks (41/152 [27%] to 50/150 [33%], aRR: 1.09 [95% CI, 1.05–1.14]) and 24 weeks (156/248 [63%] to 174/269 [65%], aRR: 1.05 [95% CI, 1.03–1.07]), with smaller relative increases for infants 25 and 27 weeks and no change for infants 22, 26 and 28 weeks. Survival without major morbidity increased approximately 2% per year for infants 25–28 weeks with no change for infants 22–24 weeks.
Conclusions and Relevance
Among extremely preterm infants born at US academic centers over the last 20 years, changes in maternal and infant care practices and modest reductions in several morbidities were observed, although bronchopulmonary dysplasia increased. Survival increased most markedly for infants born at 23 and 24 weeks and survival without major morbidity increased for infants 25–28 weeks. These findings may be valuable in counselling families and developing novel interventions.
PMCID: PMC4787615  PMID: 26348753
3.  Cognitive Outcomes After Neonatal Encephalopathy 
Pediatrics  2015;135(3):e624-e634.
To describe the spectrum of cognitive outcomes of children with and without cerebral palsy (CP) after neonatal encephalopathy, evaluate the prognostic value of early developmental testing and report on school services and additional therapies.
The participants of this study are the school-aged survivors of the National Institute of Child Health and Human Development Neonatal Research Network randomized controlled trial of whole-body hypothermia. Children underwent neurologic examinations and neurodevelopmental and cognitive testing with the Bayley Scales of Infant Development–II at 18 to 22 months and the Wechsler intelligence scales and the Neuropsychological Assessment–Developmental Neuropsychological Assessment at 6 to 7 years. Parents were interviewed about functional status and receipt of school and support services. We explored predictors of cognitive outcome by using multiple regression models.
Subnormal IQ scores were identified in more than a quarter of the children: 96% of survivors with CP had an IQ <70, 9% of children without CP had an IQ <70, and 31% had an IQ of 70 to 84. Children with a mental developmental index <70 at 18 months had, on average, an adjusted IQ at 6 to 7 years that was 42 points lower than that of those with a mental developmental index >84 (95% confidence interval, −49.3 to −35.0; P < .001). Twenty percent of children with normal IQ and 28% of those with IQ scores of 70 to 84 received special educational support services or were held back ≥1 grade level.
Cognitive impairment remains an important concern for all children with neonatal encephalopathy.
PMCID: PMC4338321  PMID: 25713280
neonatal encephalopathy; cognitive outcomes; hypoxic ischemic encephalopathy
4.  PaCO2 in Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT) 
To determine the association of PaCO2 with severe intraventricular hemorrhage (sIVH), bronchopulmonary dysplasia (BPD), and neurodevelopmental impairment (NDI) at 18–22 months in premature infants.
Secondary exploratory data analysis of SUPPORT.
Multiple referral NICUs.
1316 infants 24 0/7 to 27 6/7 weeks gestation randomized to different oxygenation (SpO2 target 85–89% vs 91–95%) and ventilation strategies.
Main Outcome Measures
Blood gases from postnatal days 0–14 were analyzed. Five PaCO2 variables were defined: minimum [Min], maximum [Max], standard deviation, average (time-weighted), and a 4 level categorical variable (hypercapnic [highest quartile of Max PaCO2], hypocapnic [lowest quartile of Min PaCO2], fluctuators [both hypercapnia and hypocapnia], and normocapnic [middle two quartiles of Max and Min PaCO2]). PaCO2 variables were compared for infants with and without sIVH, BPD, and NDI (+/− death). Multivariable logistic regression models were developed for adjusted results.
sIVH, BPD, and NDI (+/− death) were associated with hypercapnic infants and fluctuators. Association of Max PaCO2 and outcomes persisted after adjustment (Per 10 mmHg increase: sIVH/death: OR 1.27 [1.13–1.41]; BPD/death: OR 1.27 [1.12–1.44]; NDI/death: OR 1.23 [1.10–1.38], Death: OR 1.27 [1.12–1.44], all p <0.001). No interaction was found between PaCO2 category and SpO2 treatment group for sIVH/death, NDI/death, or death. Max PaCO2 was positively correlated with maximum FiO2 (rs0.55, p<0.0001) & ventilator days (rs0.61, p<0.0001).
Higher PaCO2 was an independent predictor of sIVH/death, BPD/death, and NDI/death. Further trials are needed to evaluate optimal PaCO2 targets for high risk infants.
PMCID: PMC4336211  PMID: 25425651
Infant; premature; Infant mortality; Infant; Premature; Diseases/epidemiology; Predictive value of tests; Prognosis; Intracranial hemorrhage; Blood Gas Analysis
5.  Neonatal Magnetic Resonance Imaging Pattern of Brain Injury as a Biomarker of Childhood Outcomes following a Trial of Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy 
The Journal of pediatrics  2015;167(5):987-993.e3.
To examine the ability of magnetic resonance imaging (MRI) patterns of neonatal brain injury defined by the National Institute of Child Health and Human Development Neonatal Research Network to predict death or IQ at 6–7 years of age following hypothermia for neonatal encephalopathy.
Study design
Out of 208 participants, 124 had MRI and primary outcome (death or IQ <70) data. The relationship between injury pattern and outcome was assessed.
Death or IQ <70 occurred in 4 of 50 (8%) of children with pattern 0 (normal MRI), 1 of 6 (17%) with 1A (minimal cerebral lesions), 1 of 4 (25%) with 1B (extensive cerebral lesions), 3 of 8 (38%) with 2A (basal ganglia thalamic, anterior or posterior limb of internal capsule, or watershed infarction), 32 of 49 (65%) with 2B (2A with cerebral lesions), and 7 of 7 (100%) with pattern 3 (hemispheric devastation), P < .001; this association was also seen within hypothermia and control subgroups. IQ was 90 ± 13 among the 46 children with a normal MRI and 69 ± 25 among the 50 children with an abnormal MRI. In childhood, for a normal outcome, a normal neonatal MRI had a sensitivity of 61%, specificity of 92%, a positive predictive value of 92%, and a negative predictive value of 59%; for death or IQ <70, the 2B and 3 pattern combined had a sensitivity of 81%, specificity of 78%, positive predictive value of 70%, and a negative predictive value of 87%.
The Neonatal Research Network MRI pattern of neonatal brain injury is a biomarker of neurodevelopmental outcome at 6–7 years of age.
PMCID: PMC4700815  PMID: 26387012
6.  Screening Cranial Imaging at Multiple Time Points Improves Cystic Periventricular Leukomalacia Detection 
American journal of perinatology  2015;32(10):973-979.
The aim of this study is to determine whether the cystic periventricular leukomalacia (cPVL) detection rate differs between imaging studies performed at different time points.
We retrospectively reviewed the prospectively collected data of 31,708 infants from the NICHD Neonatal Research Network. Inclusion criteria were infants < 1,000 g birth weight or < 29 weeks’ gestational age who had cranial imaging performed using both early criterion (cranial ultrasound [CUS] < 28 days chronological age) and late criterion (CUS, magnetic resonance imaging, or computed tomography closest to 36 weeks postmenstrual age [PMA]). We compared the frequency of cPVL diagnosed by early and late criteria.
About 664 (5.2%) of the 12,739 infants who met inclusion criteria had cPVL using either early or late criteria; 569 using the late criterion, 250 using the early criterion, and 155 patients at both times. About 95 (14.3%) of 664 cPVL cases seen on early imaging were no longer visible on repeat screening closest to 36 weeks PMA. Such disappearance of cPVL was more common in infants < 26 weeks’ gestation versus infants of 26 to 28 weeks’ gestation (18.5 vs. 11.5%; p = 0.013).
Cranial imaging at both < 28 days chronological age and closest to 36 weeks PMA improves cPVL detection, especially for more premature infants.
PMCID: PMC4697863  PMID: 25730135
cystic periventricular leukomalacia; screening cranial imaging; extremely low birth weight preterm infants
7.  Definitions of cardiovascular insufficiency and relation to outcomes in critically ill newborn infants 
American journal of perinatology  2015;32(11):1024-1030.
We previously reported on the overall incidence, management and outcomes in infants with cardiovascular insufficiency (CVI). However, there are limited data on the relationship of the specific different definitions of CVI to short term outcomes in term and late preterm newborn infants.
To evaluate how 4 definitions of CVI relate to short term outcomes and death.
Study Design
The previously reported study was a multicenter, prospective cohort study of 647 infants ≥ 34 weeks gestation admitted to a Neonatal Research Network (NRN) newborn intensive care unit (NICU) and mechanically ventilated (MV) during their first 72 hours. The relationship of five short term outcomes at discharge and 4 different definitions of CVI were further analyzed.
All 4 definitions were associated with greater number of days on MV & days on O2. The definition using a threshold blood pressure (BP) measurement alone was not associated with days to full feeding, days in the NICU or death. The definition based on treatment of CVI was associated with all outcomes including death.
The definition using a threshold BP alone was not consistently associated with adverse short term outcomes. Using only a threshold BP to determine therapy may not improve outcomes.
PMCID: PMC4689139  PMID: 25825962
blood pressure; cardiovascular insufficiency; outcomes; newborn; infant
8.  Temperature Control During Therapeutic Hypothermia for Newborn Encephalopathy Using Different Blanketrol Devices 
Therapeutic hypothermia improves the survival and neurodevelopmental outcome of infants with newborn encephalopathy of a hypoxic-ischemic origin. The NICHD Neonatal Research Network (NRN) Whole Body Cooling trial used the Cincinnati Sub-Zero Blanketrol II to achieve therapeutic hypothermia. The Blanketrol III is now available and provides additional cooling modes that may result in better temperature control. This report is a retrospective comparison of infants undergoing hypothermia using two different cooling modes of the Blanketrol device. Infants from the NRN trial were cooled with the Blanketrol II using the Automatic control mode (B2 cohort) and were compared with infants from two new NRN centers that adopted the NRN protocol and used the Blanketrol III in a gradient mode (B3 cohort). The primary outcome was the percent time the esophageal temperature stayed between 33°C and 34°C (target 33.5°C) during maintenance of hypothermia. Cohorts had similar birth weight, gestational age, and level of encephalopathy at the initiation of therapy. Baseline esophageal temperature differed between groups (36.6°C±1.0°C for B2 vs. 33.9°C±1.2°C for B3, p<0.0001) reflecting the practice of passive cooling during transport prior to initiation of active device cooling in the B3 cohort. This difference prevented comparison of temperatures during induction of hypothermia. During maintenance of hypothermia the mean and standard deviation of the percent time between 33°C and 34°C was similar for B2 compared to B3 cohorts (94.8%±0.1% vs. 95.8%±0.1%, respectively). Both the automatic and gradient control modes of the Blanketrol devices appear comparable in maintaining esophageal temperature within the target range during maintenance of therapeutic hypothermia.
PMCID: PMC4267126  PMID: 25285767
9.  Between-Hospital Variation in Treatment and Outcomes in Extremely Preterm Infants 
The New England journal of medicine  2015;372(19):1801-1811.
Between-hospital variation in outcomes among extremely preterm infants is largely unexplained and may reflect differences in hospital practices regarding the initiation of active lifesaving treatment as compared with comfort care after birth.
We studied infants born between April 2006 and March 2011 at 24 hospitals included in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Data were collected for 4987 infants born before 27 weeks of gestation without congenital anomalies. Active treatment was defined as any potentially lifesaving intervention administered after birth. Survival and neurodevelopmental impairment at 18 to 22 months of corrected age were assessed in 4704 children (94.3%).
Overall rates of active treatment ranged from 22.1% (interquartile range [IQR], 7.7 to 100) among infants born at 22 weeks of gestation to 99.8% (IQR, 100 to 100) among those born at 26 weeks of gestation. Overall rates of survival and survival without severe impairment ranged from 5.1% (IQR, 0 to 10.6) and 3.4% (IQR, 0 to 6.9), respectively, among children born at 22 weeks of gestation to 81.4% (IQR, 78.2 to 84.0) and 75.6% (IQR, 69.5 to 80.0), respectively, among those born at 26 weeks of gestation. Hospital rates of active treatment accounted for 78% and 75% of the between-hospital variation in survival and survival without severe impairment, respectively, among children born at 22 or 23 weeks of gestation, and accounted for 22% and 16%, respectively, among those born at 24 weeks of gestation, but the rates did not account for any of the variation in outcomes among those born at 25 or 26 weeks of gestation.
Differences in hospital practices regarding the initiation of active treatment in infants born at 22, 23, or 24 weeks of gestation explain some of the between-hospital variation in survival and survival without impairment among such patients. (Funded by the National Institutes of Health.)
PMCID: PMC4465092  PMID: 25946279
10.  Prophylactic Indomethacin and Intestinal Perforation in Extremely Low Birth Weight Infants 
Pediatrics  2014;134(5):e1369-e1377.
Prophylactic indomethacin reduces severe intraventricular hemorrhage but may increase spontaneous intestinal perforation (SIP) in extremely low birth weight (ELBW) infants. Early feedings improve nutritional outcomes but may increase the risk of SIP. Despite their benefits, use of these therapies varies largely by physician preferences in part because of the concern for SIP.
This was a cohort study of 15 751 ELBW infants in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network from 1999 to 2010 who survived beyond 12 hours after birth. The risk of SIP was compared between groups of infants with and without exposure to prophylactic indomethacin and early feeding in unadjusted analyses and in analyses adjusted for center and for risks of SIP.
Among infants exposed to prophylactic indomethacin, the risk of SIP did not differ between the indomethacin/early-feeding group compared with the indomethacin/no-early-feeding group (adjusted relative risk [RR] 0.74, 95% confidence interval [CI] 0.49–1.11). The risk of SIP was lower in the indomethacin/early-feeding group compared with the no indomethacin/no-early-feeding group (adjusted RR 0.58, 95% CI 0.37–0.90, P = .0159). Among infants not exposed to indomethacin, early feeding was associated with a lower risk of SIP compared with the no early feeding group (adjusted RR 0.53, 95% CI 0.36–0.777, P = .0011).
The combined or individual use of prophylactic indomethacin and early feeding was not associated with an increased risk of SIP in ELBW infants.
PMCID: PMC4533280  PMID: 25349317
indomethacin; intestinal perforation; necrotizing enterocolitis; neonate
11.  Serial aEEG recordings in a cohort of extremely preterm infants: feasibility and safety 
Amplitude-integrated EEG (aEEG) monitoring is increasing in the neonatal population, but the safety and feasibility of performing aEEG in extremely preterm infants have not been systematically evaluated.
Inborn infants 230/7 – 286/7 weeks gestation or birth weight 401–1000 grams were eligible. Serial, six-hour aEEG recordings were obtained from first week of life until 36 weeks postmenstrual age. Adverse events were documented, and surveys evaluated the impact of the aEEGs on routine care. Success of performing aEEGs according to protocol and aEEG quality were assessed.
102 infants were enrolled, with 755 recordings performed. 83% of recordings were performed according to schedule, and 96% were without adverse event. Bedside nurses reported no interference with routine care for 89% of recordings. 92% of recordings had acceptable signal quality.
Serial aEEG monitoring is safe in preterm infants, with few adverse events and general acceptance by nursing staff.
PMCID: PMC4414657  PMID: 25474559
12.  Surgery and Neurodevelopmental Outcome of Very Low Birth Weight Infants 
JAMA pediatrics  2014;168(8):746-754.
Reduced death and neurodevelopmental impairment among infants is a goal of perinatal medicine.
To assess the association between surgery during the initial hospitalization and death or neurodevelopmental impairment of very low birth weight infants.
Retrospective cohort analysis of patients enrolled in the National Institute of Child Health and Human Development Neonatal Research Network Generic Database from 1998–2009 and evaluated at 18–22 months’ corrected age.
22 academic neonatal intensive care units.
Inclusion criteria were: birth weight 401–1500 g; survival to 12 hours; available for follow-up. Some conditions were excluded. 12 111 infants were included in analyses, 87% of those eligible.
Surgical procedures; surgery also classified by expected anesthesia type as major (general anesthesia) or minor surgery (non-general anesthesia).
Multivariable logistic regression analyses planned a priori were performed for the primary outcome of death or neurodevelopmental impairment and for the secondary outcome of neurodevelopmental impairment among survivors. Multivariable linear regression analyses were performed as planned for the adjusted means of Bayley Scales of Infant Development, Second Edition, Mental Developmental Index and Psychomotor Developmental Index for patients born before 2006.
There were 2186 major, 784 minor and 9141 no surgery patients. The risk-adjusted odds ratio of death or neurodevelopmental impairment for all surgery patients compared with those who had no surgery was 1.29 (95% confidence interval 1.08–1.55). For patients who had major surgery compared with those who had no surgery the risk-adjusted odds ratio of death or neurodevelopmental impairment was 1.52 (95% confidence interval 1.24–1.87). Patients classified as having minor surgery had no increased adjusted risk. Among survivors who had major surgery compared with those who had no surgery the adjusted odds ratio for neurodevelopmental impairment was 1.56 (95% confidence interval 1.26–1.93) and the adjusted mean Mental Developmental Index and mean Psychomotor Developmental Index values were lower.
Major surgery in very low birth weight infants is independently associated with a greater than 50% increased risk of death or neurodevelopmental impairment and of neurodevelopmental impairment at 18–22 months’ corrected age. The role of general anesthesia is implicated but remains unproven.
PMCID: PMC4142429  PMID: 24934607
13.  Causes and Timing of Death in Extremely Premature Infants from 2000 through 2011 
The New England journal of medicine  2015;372(4):331-340.
Understanding the causes and timing of death in extremely premature infants may guide research efforts and inform the counseling of families.
We analyzed prospectively collected data on 6075 deaths among 22,248 live births, with gestational ages of 22 0/7 to 28 6/7 weeks, among infants born in study hospitals within the National Institute of Child Health and Human Development Neonatal Research Network. We compared overall and cause-specific in-hospital mortality across three periods from 2000 through 2011, with adjustment for baseline differences.
The number of deaths per 1000 live births was 275 (95% confidence interval [CI], 264 to 285) from 2000 through 2003 and 285 (95% CI, 275 to 295) from 2004 through 2007; the number decreased to 258 (95% CI, 248 to 268) in the 2008–2011 period (P = 0.003 for the comparison across three periods). There were fewer pulmonary-related deaths attributed to the respiratory distress syndrome and bronchopulmonary dysplasia in 2008–2011 than in 2000–2003 and 2004–2007 (68 [95% CI, 63 to 74] vs. 83 [95% CI, 77 to 90] and 84 [95% CI, 78 to 90] per 1000 live births, respectively; P = 0.002). Similarly, in 2008–2011, as compared with 2000–2003, there were decreases in deaths attributed to immaturity (P = 0.05) and deaths complicated by infection (P = 0.04) or central nervous system injury (P<0.001); however, there were increases in deaths attributed to necrotizing enterocolitis (30 [95% CI, 27 to 34] vs. 23 [95% CI, 20 to 27], P = 0.03). Overall, 40.4% of deaths occurred within 12 hours after birth, and 17.3% occurred after 28 days.
We found that from 2000 through 2011, overall mortality declined among extremely premature infants. Deaths related to pulmonary causes, immaturity, infection, and central nervous system injury decreased, while necrotizing enterocolitis–related deaths increased. (Funded by the National Institutes of Health.)
PMCID: PMC4349362  PMID: 25607427
14.  Developmental Outcomes of Very Preterm Infants with Tracheostomies 
The Journal of pediatrics  2014;164(6):1303-1310.e2.
To evaluate the neurodevelopmental outcomes of very preterm (<30 weeks) infants who underwent tracheostomy.
Study design
Retrospective cohort study from 16 centers of the NICHD Neonatal Research Network over 10 years (2001-2011). Infants who survived to at least 36 weeks (N=8,683), including 304 infants with tracheostomies, were studied. Primary outcome was death or neurodevelopmental impairment (NDI, a composite of one or more of: developmental delay, neurologic impairment, profound hearing loss, severe visual impairment) at a corrected age of 18-22 months. Outcomes were compared using multiple logistic regression. We assessed impact of timing, by comparing outcomes of infants who underwent tracheostomy before and after 120 days of life.
Tracheostomies were associated with all neonatal morbidities examined, and with most adverse neurodevelopmental outcomes. Death or NDI occurred in 83% of infants with tracheostomies and 40% of those without [odds ratio (OR) adjusted for center 7.0 (95%CI, 5.2-9.5)]. After adjustment for potential confounders, odds of death or NDI remained higher [OR 3.3 (95%CI, 2.4-4.6)], but odds of death alone were lower [OR 0.4 (95%CI, 0.3-0.7)], among infants with tracheostomies. Death or NDI was lower in infants who received their tracheostomies before, rather than after, 120 days of life [adjusted OR 0.5 (95%CI, 0.3-0.9)].
Tracheostomy in preterm infants is associated with adverse developmental outcomes, and cannot mitigate the significant risk associated with many complications of prematurity. These data may inform counseling about tracheostomy in this vulnerable population.
PMCID: PMC4035374  PMID: 24472229
newborn; very low birth weight infant; neurodevelopmental impairment; tracheotomy; bronchopulmonary dysplasia; prematurity
15.  Effect of Depth and Duration of Cooling on Deaths in the NICU Among Neonates With Hypoxic Ischemic Encephalopathy 
JAMA  2014;312(24):2629-2639.
Hypothermia at 33.5°C for 72 hours for neonatal hypoxic ischemic encephalopathy reduces death or disability to 44% to 55%; longer cooling and deeper cooling are neuroprotective in animal models.
To determine if longer duration cooling (120 hours), deeper cooling (32.0°C), or both are superior to cooling at 33.5°C for 72 hours in neonates who are full-term with moderate or severe hypoxic ischemic encephalopathy.
Arandomized, 2 × 2 factorial design clinical trial performed in 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network between October 2010 and November 2013.
Neonates were assigned to 4 hypothermia groups; 33.5°C for 72 hours, 32.0°C for 72 hours, 33.5°C for 120 hours, and 32.0°C for 120 hours.
The primary outcome of death or disability at 18 to 22 months is ongoing. The independent data and safety monitoring committee paused the trial to evaluate safety (cardiac arrhythmia, persistent acidosis, major vessel thrombosis and bleeding, and death in the neonatal intensive care unit [NICU]) after the first 50 neonates were enrolled, then after every subsequent 25 neonates. The trial was closed for emerging safety profile and futility analysis after the eighth review with 364 neonates enrolled (of 726 planned). This report focuses on safety and NICU deaths by marginal comparisons of 72 hours’ vs 120 hours’ duration and 33.5°C depth vs 32.0°C depth (predefined secondary outcomes).
The NICU death rates were 7 of 95 neonates (7%) for the 33.5°C for 72 hours group, 13 of 90 neonates (14%) for the 32.0°C for 72 hours group, 15 of 96 neonates (16%) for the 33.5°C for 120 hours group, and 14 of 83 neonates (17%) for the 32.0°C for 120 hours group. The adjusted risk ratio (RR) for NICU deaths for the 120 hours group vs 72 hours group was 1.37 (95% CI, 0.92–2.04) and for the 32.0°C group vs 33.5°C group was 1.24 (95% CI, 0.69–2.25). Safety outcomes were similar between the 120 hours group vs 72 hours group and the 32.0°C group vs 33.5°C group, except major bleeding occurred among 1% in the 120 hours group vs 3% in the 72 hours group (RR, 0.25 [95% CI, 0.07–0.91]). Futility analysis determined that the probability of detecting a statistically significant benefit for longer cooling, deeper cooling, or both for NICU death was less than 2%.
Among neonates who were full-term with moderate or severe hypoxic ischemic encephalopathy, longer cooling, deeper cooling, or both compared with hypothermia at 33.5°C for 72 hours did not reduce NICU death. These results have implications for patient care and design of future trials.
PMCID: PMC4335311  PMID: 25536254
16.  Inhaled Nitric Oxide Usage in Preterm Infants in the NICHD Neonatal Research Network: Inter-site Variation and Propensity Evaluation 
The use of inhaled nitric oxide (iNO) in preterm infants remains controversial. In October 2010, an NIH consensus development conference cautioned against use of iNO in preterm infants.
1) To determine prevalence and variability in use of iNO in the NICHD Neonatal Research Network (NRN) before and after the consensus conference and 2) separately, to examine associations between iNO use and severe BPD or death.
The NICHD NRN Generic Database collects data including iNO use on very preterm infants. A total of 13 centers contributed data across the time period 2008–2011. Infants exposed or not to iNO were compared using logistic regression, which included factors related to risk as well as their likelihood of being exposed to iNO.
A total of 4,885 infants were assessed between 2008–2011; 128 (2.6%) received iNO before Day 7, 140 (2.9%) between Day 7 and 28 and 47 (1.0%) at >28 days. Center-specific iNO use during 2008–2010 ranged from 21.9% to 0.4%; 12 of 13 sites reduced usage and overall NRN iNO usage decreased from 4.6% to 1.6% (p<0.001) in 2011. Use of iNO started between Day 7 and Day 14 was more prevalent among younger infants with more severe courses in Week 1 and associated with increased risk of severe BPD or death (OR 2.24;95% CI 1.23–4.07).
The variability and total use of iNO decreased in 2011 compared to 2008–2010. iNO administration started at ≥Day 7 was associated with more severe outcomes compared to infants without iNO exposure.
PMCID: PMC4323079  PMID: 24901452
Inhaled nitric oxide; bronchopulmonary dysplasia; extremely premature infant
17.  Mortality and Morbidity of VLBW Infants With Trisomy 13 or Trisomy 18 
Pediatrics  2014;133(2):226-235.
Little is known about how very low birth weight (VLBW) affects survival and morbidities among infants with trisomy 13 (T13) or trisomy 18 (T18). We examined the care plans for VLBW infants with T13 or T18 and compared their risks of mortality and neonatal morbidities with VLBW infants with trisomy 21 and VLBW infants without birth defects.
Infants with birth weight 401 to 1500 g born or cared for at a participating center of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network during the period 1994–2009 were studied. Poisson regression models were used to examine risk of death and neonatal morbidities among infants with T13 or T18.
Of 52 262 VLBW infants, 38 (0.07%) had T13 and 128 (0.24%) had T18. Intensity of care in the delivery room varied depending on whether the trisomy was diagnosed before or after birth. The plan for subsequent care for the majority of the infants was to withdraw care or to provide comfort care. Eleven percent of infants with T13 and 9% of infants with T18 survived to hospital discharge. Survivors with T13 or T18 had significantly increased risk of patent ductus arteriosus and respiratory distress syndrome compared with infants without birth defects. No infant with T13 or T18 developed necrotizing enterocolitis.
In this cohort of liveborn VLBW infants with T13 or T18, the timing of trisomy diagnosis affected the plan for care, survival was poor, and death usually occurred early.
PMCID: PMC3904274  PMID: 24446439
trisomy 13; trisomy 18; trisomy 21; very low birth weight; preterm infants
18.  Chorioamnionitis and Early Childhood Outcomes among Extremely Low-Gestational-Age Neonates 
JAMA pediatrics  2014;168(2):137-147.
Chorioamnionitis is strongly linked to preterm birth and to neonatal infection. The association between histological and clinical chorioamnionitis and cognitive, behavioral and neurodevelopmental outcomes among extremely preterm neonates is less clear. We evaluated the impact of chorioamnionitis on 18-22 month neurodevelopmental outcomes in a contemporary cohort of extremely preterm neonates.
To compare the neonatal and neurodevelopmental outcomes of three groups of extremely-low-gestational-age infants with increasing exposure to perinatal inflammation: no chorioamnionitis, histological chorioamnionitis alone, or histological plus clinical chorioamnionitis.
Longitudinal observational study.
Sixteen centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.
2390 extremely preterm infants born <27 weeks' gestational age between January 1, 2006 and December 31, 2008 with placental histopathology and 18-22 months' corrected age follow-up data were eligible.
Main exposure
Main Outcome Measures
Outcomes included cerebral palsy, gross motor functional limitation, behavioral scores (according to the Brief Infant-Toddler Social and Emotional Assessment), cognitive and language scores (according to the Bayley Scales of Infant Development, 3rd-Edition) and composite measures of death/neurodevelopmental impairment. Multivariable logistic and linear regression models were developed to assess the association between chorioamnionitis and outcomes while controlling for important variables known at birth.
Neonates exposed to chorioamnionitis had a lower gestational age (GA) and had higher rates of early-onset sepsis and severe periventricular-intraventricular hemorrhage as compared with unexposed neonates. In multivariable models evaluating death and neurodevelopmental outcomes, inclusion of gestational age in the model diminished the association between chorioamnionitis and adverse outcomes. Still, histological+clinical chorioamnionitis was associated with increased risk of cognitive impairment as compared with no chorioamnionitis (Adjusted OR 2.4, [1.3- 4.3] without GA; Adjusted OR 2.0, [1.1-3.6] with GA as a covariate). Histological chorioamnionitis alone was associated with lower odds of death/neurodevelopmental impairment as compared with histological+clinical chorioamnionitis (Adjusted OR 0.68, [0.52-0.89] without GA; 0.66, [0.49-0.89] with GA). Risk of behavioral problems did not differ statistically between groups.
Conclusions and Relevance
Antenatal exposure to chorioamnionitis is associated with altered odds of cognitive impairment and death/neurodevelopmental impairment in extremely preterm infants.
PMCID: PMC4219500  PMID: 24378638
chorioamnionitis; preterm; neurodevelopmental impairment; outcome
19.  Death or Neurodevelopmental Impairment at 18 To 22 Months in a Randomized Trial of Early Dexamethasone to Prevent Death or Chronic Lung Disease in Extremely Low Birth Weight Infants 
The Journal of pediatrics  2013;164(1):34-39.e2.
To evaluate the incidence of death or neurodevelopmental impairment (NDI) at 18 to 22 months corrected age in subjects enrolled in a trial of early dexamethasone treatment to prevent death or chronic lung disease in extremely low birth weight infants.
Evaluation of infants at 18 to 22 months corrected age included anthropomorphic measurements, a standard neurological examination, and the Bayley Scales of Infant Development-II, including the Mental Developmental Index (MDI) and the Psychomotor Developmental Index (PDI). NDI was defined as moderate or severe cerebral palsy, MDI or PDI less than 70, blindness, or hearing impairment.
Death or NDI at 18 to 22 months corrected age was similar in the dexamethasone and placebo groups (65 vs 66 percent, p= 0.99 among those with known outcome). The proportion of survivors with NDI was also similar, as were mean values for weight, length, and head circumference and the proportion of infants with poor growth (50 vs 41 percent, p=0.42 for weight less than 10th percentile). Forty nine percent of infants in the placebo group received treatment with corticosteroid compared to 32% in the dexamethasone group (p=0.02).
The risk of death or NDI and rate of poor growth were high but similar in the dexamethasone and placebo groups. The lack of a discernible effect of early dexamethasone on neurodevelopmental outcome may be due to frequent clinical corticosteroid use in the placebo group.
PMCID: PMC4120744  PMID: 23992673
neurodevelopmental outcome; growth; bronchopulmonary dysplasia; cerebral palsy; neonatal follow-up
20.  Outcomes of Extremely Low Birth Weight Infants with Acidosis at Birth 
To test the hypothesis that acidosis at birth is associated with the combined primary outcome of death or neurodevelopmental impairment (NDI) in extremely low birth weight (ELBW) infants, and to develop a predictive model of death/NDI exploring perinatal acidosis as a predictor variable.
The study population consisted of ELBW infants born between 2002-2007 at NICHD Neonatal Research Network hospitals. Infants with cord blood gas data and documentation of either mortality prior to discharge or 18-22 month neurodevelopmental outcomes were included. Multiple logistic regression analysis was used to determine the contribution of perinatal acidosis, defined as a cord blood gas with a pH<7 or base excess (BE)<-12, to death/NDI in ELBW infants. In addition, a multivariable model predicting death/NDI was developed.
3979 patients were identified of whom 249 had a cord gas pH<7 or BE<-12 mEq/L. 2124 patients (53%) had the primary outcome of death/NDI. After adjustment for confounding variables, pH<7 and BE<-12 mEq/L were each significantly associated with death/NDI (OR=2.5[1.6,4.2]; and OR=1.5[1.1,2.0], respectively). However, inclusion of pH or BE did not improve the ability of the multivariable model to predict death/NDI.
Perinatal acidosis is significantly associated with death/NDI in ELBW infants. Perinatal acidosis is infrequent in ELBW infants, however, and other factors are more important in predicting death/NDI.
PMCID: PMC4274605  PMID: 24554564
Cord blood gas; Premature infant; Preterm infant; Neurodevelopmental impairment
21.  Inhaled PGE1 in neonates with hypoxemic respiratory failure: two pilot feasibility randomized clinical trials 
Trials  2014;15:486.
Inhaled nitric oxide (INO), a selective pulmonary vasodilator, has revolutionized the treatment of neonatal hypoxemic respiratory failure (NHRF). However, there is lack of sustained improvement in 30 to 46% of infants. Aerosolized prostaglandins I2 (PGI2) and E1 (PGE1) have been reported to be effective selective pulmonary vasodilators. The objective of this study was to evaluate the feasibility of a randomized controlled trial (RCT) of inhaled PGE1 (IPGE1) in NHRF.
Two pilot multicenter phase II RCTs are included in this report. In the first pilot, late preterm and term neonates with NHRF, who had an oxygenation index (OI) of ≥15 and <25 on two arterial blood gases and had not previously received INO, were randomly assigned to receive two doses of IPGE1 (300 and 150 ng/kg/min) or placebo. The primary outcome was the enrollment of 50 infants in six to nine months at 10 sites. The first pilot was halted after four months for failure to enroll a single infant. The most common cause for non-enrollment was prior initiation of INO. In a re-designed second pilot, co-administration of IPGE1 and INO was permitted. Infants with suboptimal response to INO received either aerosolized saline or IPGE1 at a low (150 ng/kg/min) or high dose (300 ng/kg/min) for a maximum duration of 72 hours. The primary outcome was the recruitment of an adequate number of patients (n = 50) in a nine-month-period, with fewer than 20% protocol violations.
No infants were enrolled in the first pilot. Seven patients were enrolled in the second pilot; three in the control, two in the low-dose IPGE1, and two in the high-dose IPGE1 groups. The study was halted for recruitment futility after approximately six months as enrollment targets were not met. No serious adverse events, one minor protocol deviation and one pharmacy protocol violation were reported.
These two pilot RCTs failed to recruit adequate eligible newborns with NHRF. Complex management RCTs of novel therapies for persistent pulmonary hypertension of the newborn (PPHN) may require novel study designs and a longer period of time from study approval to commencement of enrollment.
Trial registration:
Pilot one: NCT number: 00598429 registered on 10 January 2008. Last updated: 3 February 2011.
Pilot two: NCT number: 01467076 17 October 2011. Last updated: 13 February 2013.
Electronic supplementary material
The online version of this article (doi:10.1186/1745-6215-15-486) contains supplementary material, which is available to authorized users.
PMCID: PMC4414424  PMID: 25496504
Hypoxemic respiratory failure; Neonatal; Pulmonary hypertension; Aerosols; Nebulizers; Prostaglandins; Clinical trial
22.  Serum Tocopherol Levels in Very Preterm Infants After a Single Dose of Vitamin E at Birth 
Pediatrics  2013;132(6):e1626-e1633.
Our aim was to examine the impact of a single enteral dose of vitamin E on serum tocopherol levels. The study was undertaken to see whether a single dose of vitamin E soon after birth can rapidly increase the low α-tocopherol levels seen in very preterm infants. If so, this intervention could be tested as a means of reducing the risk of intracranial hemorrhage.
Ninety-three infants <27 weeks’ gestation and <1000 g were randomly assigned to receive a single dose of vitamin E or placebo by gastric tube within 4 hours of birth. The vitamin E group received 50 IU/kg of vitamin E as dl-α-tocopheryl acetate (Aquasol E). The placebo group received sterile water. Blood samples were taken for measurement of serum tocopherol levels by high-performance liquid chromatography before dosing and 24 hours and 7 days after dosing.
Eighty-eight infants received the study drug and were included in the analyses. The α-tocopherol levels were similar between the groups at baseline but higher in the vitamin E group at 24 hours (median 0.63 mg/dL vs 0.42 mg/dL, P = .003) and 7 days (2.21 mg/dL vs 1.86 mg/dL, P = .04). There were no differences between groups in γ-tocopherol levels. At 24 hours, 30% of vitamin E infants and 62% of placebo infants had α-tocopherol levels <0.5 mg/dL.
A 50-IU/kg dose of vitamin E raised serum α-tocopherol levels, but to consistently achieve α-tocopherol levels >0.5 mg/dL, a higher dose or several doses of vitamin E may be needed.
PMCID: PMC3838534  PMID: 24218460
vitamin E; preterm infants
23.  Immunogenicity of Haemophilus influenzae Type b Protein Conjugate Vaccines in Very Low Birth Weight Infants 
PMCID: PMC3960569  PMID: 24569312
Infant; premature; infant; very low birth weight; Haemophilus influenzae vacines; immunization; vaccines
24.  Incidence, management and outcomes of cardiovascular insufficiency in critically ill term and late preterm newborn infants 
American journal of perinatology  2014;31(11):947-956.
To characterize the incidence, management and short term outcomes of cardiovascular insufficiency (CVI) in mechanically ventilated newborns, evaluating 4 separate pre-specified definitions.
Study Design
Multicenter, prospective cohort study of infants ≥34 weeks gestational age (GA) and on mechanical ventilation during the first 72 hours. CVI was prospectively defined as either (1) mean arterial pressure (MAP)
Of 647 who met inclusion criteria, 419 (65%) met ≥1 definition of CVI. Of these, 98% received fluid boluses, 36% inotropes and 17% corticosteroids. Of treated infants, 46% did not have CVI as defined by a MAP < GA ± signs of inadequate perfusion. Inotrope therapy was associated with increased mortality (11.1% vs. 1.3%; P < 0.05).
More than half of the infants met at least one definition of CVI. However, almost half of the treated infants met none of the definitions. Inotropic therapy was associated with increased mortality. These findings can help guide the design of future studies of CVI in newborns.
PMCID: PMC4127379  PMID: 24515617
blood pressure; cardiovascular insufficiency; mechanical ventilation; inotrope; fluid bolus; glucocorticoid; outcomes; newborn
Pediatrics  2013;132(4):e905-e914.
To evaluate the association between severity of cerebral palsy (CP) and growth to 6 to 7 years of age among children with moderate to severe (Mod/Sev) hypoxic ischemic encephalopathy (HIE). It was hypothesized that children with Mod/Sev CP would have poorer growth, lower cognitive scores, and increased rehospitalization rates compared with children with no CP (No CP).
Among 115 of 122 surviving children followed in the hypothermia trial for neonatal HIE, growth parameters and neurodevelopmental status at 18 to 22 months and 6 to 7 years were available. Group comparisons (Mod/Sev CP and No CP) with unadjusted and adjusted analyses for growth <10th percentile and z scores by using Fisher’s exact tests and regression modeling were conducted.
Children with Mod/Sev CP had high rates of slow growth and cognitive and motor impairment and rehospitalizations at 18 to 22 months and 6 to 7 years. At 6 to 7 years of age, children with Mod/Sev CP had increased rates of growth parameters <10th percentile compared with those with No CP (weight, 57% vs 3%; height, 70% vs 2%; and head circumference, 82% vs 13%; P < .0001). Increasing severity of slow growth was associated with increasing age (P < .04 for weight, P < .001 for length, and P < .0001 for head circumference). Gastrostomy feeds were associated with better growth.
Term children with HIE who develop Mod/Sev CP have high and increasing rates of growth <10th percentile by 6 to 7 years of age. These findings support the need for close medical and nutrition management of children with HIE who develop CP.
PMCID: PMC3784290  PMID: 24019415
encephalopathy; hypoxia-ischemia; hypothermia; cerebral palsy; growth

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